1-(6,7-Dimethoxyquinazol-4-yl)semicarbazides

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is hydrogen, alkyl of 1 to 4 carbon atoms or trifluoromethyl; 
     R 2 , R 3  and R 4  are each independently hydrogen, methyl or ethyl; 
     R 5  is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl-(alkyl of 1 to 8 carbon atoms), cycloalkyl of 3 to 7 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonyl-methyl, phenyl, substituted phenyl, naphthyl or substituted naphthyl; or 
     R 4  and R 5 , together with each other, are alkylene of 4 to 5 carbon atoms, optionally interrupted by --O-- or --NR 6  --, where R 6  is alkyl of 1 to 4 carbon atoms; 
     and non-toxic, pharmacologically acceptable acid addition salts thereof. The compounds as well as their salts are useful as cardiotonics.

This invention relates to novel semicarbazides and salts thereof, tomethods of preparing these compounds, to pharmaceutical compositionscontaining them as active ingredients, and to a method of using them ascardiotonics.

More particularly, the present invention relates to a novel class ofsemicarbazides represented by the formula ##STR2## wherein R₁ ishydrogen, alkyl of 1 to 4 carbon atoms or trifluoromethyl;

R₂, R₃ and R₄ are each independently hydrogen, methyl or ethyl;

R₅ is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl-(alkyl of 1 to 8carbon atoms), cycloalkyl of 3 to 7 carbon atoms, (alkoxy of 1 to 4carbon atoms) carbonyl-methyl, phenyl, substituted phenyl, naphthyl orsubstituted naphthyl; or

R₄ and R₅, together with each other, are alkylene of 4 to 5 carbonatoms, optionally interrupted by --O-- or --NR₆ --, where R₆ is alkyl of1 to 4 carbon atoms;

and non-toxic, pharmacologically acceptable acid addition salts thereof.

The alkyl moieties in the substituents defined above may be straight orbranched.

The preferred alkyl embodiments of R₁ are methyl and ethyl.

In the case of R₅, the C₁ -C₈ -alkyl moiety preferably has 3 to 5 carbonatoms, and the cycloalkyl group has 5 to 6 carbon atoms, while thealkoxy moiety in the alkoxycarbonylmethyl group is preferably methoxy orethoxy. The substituents in the aromatic groups are, in particular,methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine and CF₃.Methyl, methoxy and chlorine should be particularly emphasized. Up tothree identical or different substituents may be present. If R₄ and R₅represent an alkylene chain optionally interrupted by --0-- or --NR₆ --,they may, for example, represent a group such as --(CH₂)₄ --, --(CH₂)₅--, --CH₂ --CH₂ --O--CH₂ --CH₂ -- or --CH₂ --CH₂ --NCH₃ --CH₂ --CH₂ --.The group R₁ preferably represents H or CH₃. The substituents R₂, R₃ andR₄ preferably represent H.

The compounds embraced by formula I may be prepared by the followingmethods:

Method A

By reacting a 6,7-dimethoxy-quinazoline of the formula ##STR3## whereinX is chlorine or another substituent which can be exchanged for an aminogroup, and

R₁ has the meanings previously defined, with a semicarbazide of theformula

    HNR.sub.2 --NR.sub.3 --CO--NR.sub.4 R.sub.5                (III)

wherein R₂, R₃, R₄ and R₅ have the meanings previously defined, in asolvent which is inert under the reaction conditions.

Suitable solvents include, for example, dimethylformamide, acetonitrile,tetrahydrofuran and alkanols. Depending on the reactivity of thereactants, the reaction is carried out at temperatures between roomtemperature and the boiling point of the reaction mixture, preferablybetween 40° and 120° C., in the presence of a basic substance such assodium carbonate, potassium carbonate or a tertiary amine.

Method B

By reacting a quinazoline of the formula ##STR4## wherein R₁, R₂ and R₃have the meanings previously defined, with an isocyanate of the formula

    OCN--R.sub.5                                               (V)

wherein R₅ has the meanings previously defined, in a solvent which isinert under the reaction conditions, to yield a compound of the formulaI wherein R₄ is hydrogen.

The reaction is carried out in a solvent such as tetrahydrofuran,dioxane, ether, dimethylformamide, toluene, acetone or acetonitrile,preferably at room temperature or while gently heating. The compound ofthe formula IV may be present in suspension.

Method C

By reacting a compound of the formula IV with a carbarmoyl chloride ofthe formula

    R'.sub.4 R'.sub.5 --COCl                                   (VI)

wherein R'₄ and R'₅ have the same meanings as R₄ and R₅, respectively,with the exception of hydrogen, in a solvent which is inert under thereaction conditions. Compounds of the formula I are thus obtainedwherein R₄ and R₅ have the meanings previously defined except hydrogen.

The solvents mentioned in method B, particularly dimethylformamide, arealso suitable for use in this method. An acid-binding agent, such aspotassium carbonate or sodium carbonate, a tertiary organic base or anexcess of the amine, is conveniently used.

Method D

By reacting a compound of the formula IV with a carbamic acid ester ofthe formula

    R.sub.4 R.sub.5 N--COOR                                    (VII)

wherein R₄ and R₅ have the meanings previously defined, and R representsan optionally substituted, saturated or unsaturated, aliphatic oraraliphatic group, at elevated temperatures in a solvent which is inertunder the reaction conditions.

The solvent may be, for example, acetone, dimethylformamide or analkanol. The reaction temperature is generally between 40° and 80° C. Ifsolvents with a suitable boiling point, such as methanol, are used, thereaction may be carried out at reflux temperature.

Method E

By reacting a compound of the formula ##STR5## wherein R₁, R₂, R₃ and Rhave the meanings previously defined, with a primary or secondary amineof the formula

    HNR.sub.4 R.sub.5                                          (IX)

wherein R₄ and R₅ have the meanings previously defined, at elevatedtemperatures in a solvent which is inert under the reaction conditions.

In this process, the solvent and reaction temperatures mentioned inmethod D may be used.

If salts are obtained as the end products in methods A to E, these may,if desired, be converted into the free bases of the formula I or intosalts of other acids. The compounds embraced by formula I are basicsubstances and therefore form addition salts with inorganic or organicacids. Examples of non-toxic, pharmacologically acceptable acid additionsalts are those formed with hydrochloric, hydrobromic, sulfuric,phosphoric, lactic, citric, tartaric, maleic or fumaric acid. Thestarting compounds are known, or else may be obtained by conventionalmethods.

The following examples illustrate the present invention and will enableothers skilled in the art to understand it more completely. It should beunderstood, however, that the invention is not limited solely to theparticular examples given below.

EXAMPLE 1 1-(6,7-Dimethoxyquinazol-4-yl)-semicarbazide

2.2 g of 6,7-dimethoxy-4-chloro-quinazoline were dissolved in 50 ml ofabsolute dimethylformamide, 2.2 g of semicarbazide hydrochloride and 5 gof anhydrous potash were added thereto while stirring. The mixture wasstirred for 5 hours at 50° C., and the precipitate formed thereby wassuction-filtered off, stirred with water, and then recrystallized fromdimethylformamide. The crude product was obtained with a 30% yield; m.p.247°-249° C.

EXAMPLE 2 1-n-Butyl-4-(6,7-dimethoxyquinazol-4-yl)-semicarbazidehydrochloride

3 g of 6,7-dimethoxy-4-chloro-quinazoline were stirred with 3.5 g of4-n-butyl-semicarbazide in 100 ml of n-amyl alcohol for 2 hours at 100°C. Then, the precipitate which had formed was suction-filtered off,suspended while in hot ethanol and brought to pH 5 by the addition of 2Nhydrochloric acid. The clear solution was filtered through charcoal,cooled, suction-filtered and dried in a circulating air drier. Thehydrochloride of4-n-butyl-4-(6,7-dimethoxyquinazol-4-yl)-semi-carbazide, which wasobtained with a 70% yield, melted at 216°-217° C. The followingcompounds were obtained analogously.

1-n-Butyl-4-(6,7-dimethoxy-2-trifluoromethylquinazol-4-yl)-semicarbazidehydrochloride (Mp. 210°-212° C.).

1-n-Butyl-4-(6,7-dimethoxy-2-methylquinazol-4-yl)-semicarbazidehydrochloride (Mp. 295°-297° C.).

The following compounds were also obtained analogously, where

    __________________________________________________________________________     ##STR6##                                                                                                 Yield [in %                                                                   of theory]                                                                          Mp. [°C.]                            __________________________________________________________________________    RNHNHCONHCH.sub.2COOCH.sub.3 × HCl                                                                  48    214-5                                       RNHNHCONHCH.sub.3 × HCl                                                                             89    246-7                                        ##STR7##                   52    207-8                                        ##STR8##                   30    203-4                                       RNHNHCONHC(CH.sub.3).sub.3  × HCl                                                                   43    296-7                                       RNHNHCONHC.sub.6 H.sub.5 × HCl                                                                      57    199                                         RNHNHCONH(4-ClC.sub.6 H.sub.4)                                                                            59    198-199                                     RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4)                                                                      55    194- 95                                      ##STR9##                   35    210-211                                      ##STR10##                  35    248-51                                      RNHNHCON(CH.sub.3).sub.2 × HCl                                                                      40    246-48                                       ##STR11##                  36    287-88                                      RNHNHCON(i-C.sub.3 H.sub.7).sub.2                                                                         38    256-57                                      RNHNHCONH(CH.sub.2).sub.5CH.sub.3 × HCl                                                             73    213-214                                     RNHNHCONH(CH.sub.2).sub.4CH.sub.3 × HCl                                                             49    210-211                                     RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                                                          53    212                                         RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                                                              79    210-211                                     RNHNHCONHCH(CH.sub.3)C.sub.3 H.sub.7 × HCl                                                          56    204                                         RNHNHCONHCH(C.sub.2 H.sub.5 ).sub.2 × HCl                                                           76    218-219                                     RNHNHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                                                            84    208                                         RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                                                       77    197-199                                     RNHNHCONHC.sub.2 H.sub.5 × HCl                                                                      80    226-227                                     RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                                                   81    220-221                                     RNHNHCONH(CH.sub.2).sub.7CH.sub.3 × HCl                                                             83    208-209                                      ##STR12##                  75    207-209                                      ##STR13##                  82    200-201                                     RNHNHCONHn-C.sub.4 H.sub.9 × HCl                                                                    69    295-297                                     __________________________________________________________________________

EXAMPLE 3 1-n-Butyl-4-(6,7-dimethoxyqyinazolin-4-yl)-semicarbazidehydrochloride ##STR14##

5.12 g of 6,7-Dimethoxy-4-hydrazino-quinazoline were partially dissolvedin 200 ml of absolute acetonitrile. Then 5 ml of n-butylisocyanate wereadded thereto all at once. While the temperature rose slightly, asolution was rapidly obtained. This solution was stirred for 4 hours,and was then allowed to stand overnight. The precipitate formed therebywas suction-filtered off, dissolved in hot ethanol, and mixed with thecalculated quantity of ethanolic hydrochloric acid. The hydrochloride of1-n-butyl-4-(6,7-dimethoxy-quinazolin-4-yl)-semicarbazide crystallizedout. After cooling, it was suction-filtered off and dried in acirculating air drier. The end product, which was obtained with a 60%yield, had a melting point of 216°-217° C.

EXAMPLE 41-n-Butyl-4-(6,7-dimethoxy-2-methylquinazol-4-yl)-semicarbazidehydrochloride

2.2 of 6,7-dimethoxy-4-hydrazino-2-methyl-quinazoline were suspended in100 ml of absolute acetonitrile. 2 g of butylisocyanate were added allat once, and the mixture was stirred for 3 hours at room temperature.The base was suction-filtered off, dissolved in ethanol, and then thecalculated quantity of ethereal hydrochloric acid was added.

The hydrochloride precipitated thereby (2.3 g, 66% of theory) wassuction-filtered off and dried in a drying chamber (Mp. 295°-297° C.).

The 6,7-dimethoxy-4-hydrazino-2-methyl-quinazoline (Mp. 227°-229° C.)needed as the starting compound was obtained by reacting4-chloro-6,7-dimethoxy-2-methyl-quinazoline with excess hydrazine indimethylformamide.

Using the same procedure,1-n-butyl-4-(6,7-dimethoxy-2-trifluoromethylquinazol-4-yl)-semicarbazidehydrochloride (Mp. 210°-212° C.) was also prepared with a 73% yield.

The following compounds were synthesized in analogy to Examples 3 and 4,where R is 6,7-dimethoxyquinazolin-4-yl:

    __________________________________________________________________________                                Yield [in %                                                                   of theory]                                                                          Mp. [°C.]                            __________________________________________________________________________    RNHNHCONHCH.sub.2COOCH.sub.3 × HCl                                                                  48    214-5                                       RNHNHCONHCH.sub.3 × HCl                                                                             89    246-7                                        ##STR15##                  52    207-8                                        ##STR16##                  30    203-4                                       RNHNHCONHC(CH.sub.3).sub.3 × HCl                                                                    43    296-7                                       RNHNHCONHC.sub.6 H.sub.5 × HCl                                                                      57    199                                         RNHNHCONH(4-ClC.sub.6 H.sub.4)                                                                            63    198-199                                     RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4)                                                                      70    194-95                                       ##STR17##                  62    210-211                                     RNHNHCONH.sub.2 × HCl       247-249                                     RNHNHCONH C.sub.2 H.sub.5 × HCl                                                                     76    226-227                                     RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                                                   87    220-221                                     RNHNHCONHn-C.sub.5 H.sub.11 × HCl                                                                   50    210-211                                     RNHNHCONHCH(CH.sub.3)n-C.sub.3 H.sub.7 × HCl                                                        53    204                                         RNHNHCONHCH(C.sub.2 H.sub.5).sub.2 × HCl                                                            84    218-219                                     RNHNHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                                                            80    208                                         RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                                                       73    197-199                                     RNHNHCONHn-C.sub.6 H.sub.13 × HCl                                                                   70    213-214                                     RNHNHCONHn-C.sub.8 H.sub.17 × HCl                                                                   80    208-209                                     RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                                                              85    210-211                                     RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                                                          59    212                                          ##STR18##                  72    200-201                                      ##STR19##                  70    207-209                                     RNHNHCON(CH.sub.3).sub.2 × HCl                                                                            246-248                                     RNHNHCON(iC.sub.3 H.sub.7).sub.2 × HCl                                                                    256-257                                      ##STR20##                        248-251                                      ##STR21##                        287-288                                     __________________________________________________________________________

EXAMPLE 5 6,7-Dimethoxy-4-(2-morpholinocarbonyl)-hydrazino-quinazolinehydrochloride

2.2 g of 6,7-Dimethoxy-4-hydrazino-quinazoline were dissolved in 20 mlof dimethylformamide. 2.76 g of anhydrous potash were added, and then1.7 g of morpholinocarbamic acid chloride were added dropwise thereto,while stirring. The mixture was allowed to react for 2 hours at roomtemperature, was then poured into ice water, and the precipitate formedthereby was separated by suction filtration. The filter cake was thendissolved in ethanol and converted into the hydrochloride by theaddition of ethereal hydrochloric acid. After suction-filtering anddrying in a circulating air drier, the hydrochloride of6,7-dimethoxy-2-(2-morpholinocarbonyl)-hydrazino-quinazoline wasobtained with a 40% yield: m.p. 248°-251° C. The following compoundswere synthesized in analogy to Example 5, where R is6,7-dimethoxy-quinazolin-4-yl:

    __________________________________________________________________________                                Yield [in %                                                                   of theory]                                                                          Mp. [°C.]                            __________________________________________________________________________     ##STR22##                  30    246-248                                      ##STR23##                  35    287-288                                     RNHNHCON(i-C.sub.3 H.sub.7).sub.2                                                                         38    256-257                                     RNHNHCONH.sub.2 × HCl       247-249                                     RNHNHCONHC.sub.2 H.sub.5 × HCl                                                                      76    226-227                                     RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                                                   87    220-221                                     RNHNHCONHc-C.sub.4 H.sub.9 × HCl                                                                          216-217                                     RNHNHCONHC(CH.sub.3).sub.3 × HCl                                                                          296-297                                     RNHNHCONHn-C.sub.5 H.sub.11 × HCl                                                                   50    210-211                                     RNHNHCONHCH(CH.sub.3)n-C.sub.3 H.sub.7 × HCl                                                        53    204                                         RNHNHCONHCH(C.sub.2 H.sub.5).sub.2 × HCl                                                            84    218-219                                     RNHNHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                                                            80    208                                         RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                                                       73    197-199                                     RNHNHCONHn-C.sub.6 H.sub.13 × HCl                                                                   70    213-214                                     RNHNHCONHn-C.sub.8 H.sub.17 × HCl                                                                   80    208-209                                     RNHNHCONHC.sub.6 H.sub.5 × HCl                                                                            199                                         RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                                                              85    210-211                                     RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                                                          59    212                                          ##STR24##                  72    200-201                                      ##STR25##                  70    207-209                                     RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4) × HCl                                                                194-195                                     RNHNHCONH(4-ClC.sub.6 H.sub.4) ×  HCl                                                                     198-199                                      ##STR26##                        207-208                                      ##STR27##                        210-211                                      ##STR28##                        203-204                                     __________________________________________________________________________

EXAMPLE 6 1-Methyl-4-(6,7-dimethoxyquinazolin-4-yl)-semicarbazidehydrochloride ##STR29##

2.2 g of 6,7-dimethoxy-4-hydrazino-quinazoline were suspended in 100 mlof methanol. After the addition of 1.8 g of methyl N-methylcarbamate,the mixture was refluxed for 4 hours. The resulting clear solution wascooled, the precitate formed thereby was suction-filtered off, dissolvedagain in hot methanol, and the solution was mixed with the calculatedquantity of ethereal hydrochloric acid. This mixture was cooled, and theprecipitate was suction-filtered off and dried in a circulating airdryer. The hydrochloride of1-methyl-4-(6,7-dimethoxyquinazolin-4-yl)-semicarbazdie was obtainedwith a 50% yield; m.p. 246°-247° C.

The following compounds were prepared in analogy to Example 6, where

    __________________________________________________________________________     ##STR30##                                                                                                Yield [in %                                                                   of theory]                                                                          Mp. [°C.]                            __________________________________________________________________________    RNHNHCONHCH.sub.2 COOCH.sub.3 × HCl                                                                 48    214-15                                       ##STR31##                  52    207-8                                        ##STR32##                  30    203-4                                       RNHNHCONHC(CH.sub.3).sub.3 × HCl                                                                    43    296-7                                       RNHNHCONHC.sub.6 H.sub.5 × HCl                                                                      57    199                                         RNHNHCONH(4-ClC.sub.6 H.sub.4)                                                                            52    198-199                                     RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4)                                                                      56    194-95                                       ##STR33##                  35    210-211                                      ##STR34##                  22    248-51                                      RNHNHCON(CH.sub.3).sub.2 × HCl                                                                      28    246-48                                       ##STR35##                  35    287-88                                      RNHNHCON(i-C.sub.3 H.sub.7).sub.2                                                                         36    256-57                                      RNHNHCONH.sub.2 × HCl       247-249                                     RNHNHCONHC.sub.2 H.sub.5 × HCl                                                                            226-227                                     RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                                                         220-221                                     RNHNHCONHn-C.sub.4 H.sub.9 × HCl                                                                          216-217                                     RNHNHCONHn-C.sub.5 H.sub.11 × HCl                                                                         210-211                                     RNHNHCONHCH(CH.sub.3)C.sub.3 H.sub.7 × HCl                                                                204                                         RNHNHCONHCH(C.sub.2 H.sub.5).sub.2 × HCl                                                                  218-219                                     R NHNHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                                                                 208                                         RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                                                             197-199                                     RNHNHCONHc-C.sub.6 H.sub.13 × HCl                                                                         213-214                                     RNHNHCONHn-C.sub.8 H.sub.17 × HCl                                                                         208-209                                     RNHNHCONHCH.sub.2COOCH.sub.3 × HCl                                                                        214-215                                     RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                                                                    210-211                                     RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                                                                212                                          ##STR36##                        200-201                                      ##STR37##                        207-209                                     __________________________________________________________________________

In addition, the following compounds were prepared analogously:

1-n-Butyl-4-(6,7-dimethoxy-2-trifluoromethylquinazol-4-yl)-semicarbazidehydrochloride (Mp. 210°-212° C.).

1-n-Butyl-4-(6,7-dimethoxy-2-methylquinazol-4-yl)-semicarbazidehydrochloride (Mp. 295°-297° C.).

EXAMPLE 7 1-Methyl-4-(6,7-dimethoxyquinazolin-4-yl-semicarbazidehydrochloride

1.5 g of 6,7-dimethoxy-4-(2-carbethoxy)-hydrazino-quinazoline, which wasobtained by reacting 6,7-dimethoxy-4-hydrazino-quinazoline with ethylchlorocarbonate, were dissolved in 30 ml of dioxane. After the additionof 2 ml of a 40% methylamine solution, the mixture was heated at 60° C.for 3 hours. The precipitated crystals were suctionfiltered off,suspended in hot ethanol, then the calculated quantity of ethanolichydrochloric acid was added. A solution was rapidly obtained, which wascooled, suctionfiltered, and the filter cake was dried. Thehydrochloride of 1-methyl-4-(6,7-dimethoxyquinazolin-4-yl)-semicarbazide(Mp. 246°-7° C.) was obtained with a 20% yield.

The following compounds were prepared analogously:

1-n-Butyl-4-(6,7-dimethoxy-2-trifluoromethylquinazol-4-yl)-semicarbazidehydrochloride (Mp. 210°-212° C.).

1-n-Butyl-4-(6,7-dimethoxy-2-methylquinazol-4-yl)-semicarbazidehydrochloride (Mp. 295°-297° C.).

The following were also prepared in analogy to Example 7, where

    __________________________________________________________________________     ##STR38##                                                                                                Yield [in %                                                                   of theory]                                                                          Mp. [°C.]                            __________________________________________________________________________    RNHNHCONHCH.sub.2COOCH.sub.3 × HCl                                                                  48    214-5                                        ##STR39##                  52    207-8                                        ##STR40##                  30    203-4                                       RNHNHCONHC(CH.sub.3).sub.3 × HCl                                                                    43    206-7                                       RNHNHCONHC.sub.6 H.sub.5 × HCl                                                                      57    199                                         RNHNHCONH(4-ClC.sub.6 H.sub.4)                                                                            52    198-99                                      RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4)                                                                      46    194-95                                       ##STR41##                  42    210-11                                       ##STR42##                  35    248-51                                      RNHNHCON(CH.sub.3).sub.2 × HCl                                                                      30    246-48                                       ##STR43##                  28    287-88                                      RNHNHCON(i-C.sub.3 H.sub.7).sub.2                                                                         35    256-57                                      RNHNHCONH.sub.2 × HCl       247-249                                     RNHNHCONHC.sub.2 H.sub.5 × HCl                                                                      76    226-227                                     RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                                                   87    220-221                                     RNHNHCONHn-C.sub.4 H.sub.9 × HCl                                                                          216-217                                     RNHNHCONHn-C.sub.5 H.sub.11 × HCl                                                                   50    210-211                                     RNHNHCONHCH(CH.sub.3)n-C.sub.3 H.sub.7 × HCl                                                        53    204                                         RNHNHCONHCH(C.sub.2 H.sub.5).sub.2 × HCl                                                            84    218-219                                     RNH NHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                                                           80    208                                         RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                                                       73    197-199                                     RNHNHCONHn-C.sub.6 H.sub.13 × HCl                                                                   70    213-214                                     RNHNHCONHn-C.sub.8 H.sub.17 × HCl                                                                   80    208-209                                     RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                                                              85    210-211                                     RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                                                          59    212                                          ##STR44##                  72    200-201                                      ##STR45##                  70    207-209                                     __________________________________________________________________________

The compounds of the present invention, that is, those embraced byformula I above and non-toxic, pharmacologically acceptable acidaddition salts thereof, have useful pharmacodynamic properties. Moreparticularly, they exhibit longlasting phosphodiesterase-inhibiting andheart-stimulating activities in warm-blooded animals. They increase thecontractile force of the heart muscle without significantly affectingthe heart rate.

This selectivity, in particular, makes them useful for the therapeuticand prophylactic treatment of pathological heart conditions,particularly heart failure. Apart from their effect on heart muscle, thecompounds according to the invention also have vasodilating andhypotensive properties, and in some cases they increase the circulationof blood through the kidneys and broncholysis. The therapeutic andprophylactic dose depends on the nature and gravity of the disorder andon the route of administration.

For pharmaceutical purposes the compounds of the present invention areadministered to warm-blooded animals perorally or parenterally as activeingredients in customary pharmaceutical compositions, that is,compositions consisting essentially of an inert pharmaceutical carrierand an effective amount of the active ingredient, such as tablets,coated pills, capsules, wafers, powders, solutions, suspensions,emulsions, syrups and the like. An effective amount of the compoundsaccording to the present invention for oral administration is from 20 to1000 mg per day, administered in 2 to 4 separate doses, and theeffective amount for parenteral administration is 1 to 300 mg.

The following examples illustrate a few pharmaceutical compositionscomprising a compound of the present invention as an active ingredientand represent the best modes contemplated of using the invention. Theparts are parts by weight.

EXAMPLE 8

Tablets

The tablet composition is compounded from the following ingredients:

    ______________________________________                                        1-(6,7-dimethoxyquinazol-4-yl)-                                                                   100 parts                                                 semicarbazide                                                                 Colloidal silicic acid                                                                             10 parts                                                 Lactose             118 parts                                                 Potato starch        60 parts                                                 Polyvinylpyrrolidone                                                                               6 parts                                                  Sodium cellulose glycolate                                                                         4 parts                                                  Magnesium stearate   2 parts                                                  TOTAL               300 parts                                                 ______________________________________                                    

Preparation:

The ingredients are processed in the usual way to form 300 mg-tabletseach of which contains 100 mg of the active ingredient.

EXAMPLE 9

Capsules

The capsule filler composition is compounded from the followingingredients:

    ______________________________________                                        1-(6,7-dimethoxyquinazol-4-yl)-                                                                   200 parts                                                 semicarbazide                                                                 Corn starch         200 parts                                                 TOTAL               400 parts                                                 ______________________________________                                    

Preparation:

The ingredients are intimately admixed with each other, and 400mg-portions of the mixture are filled into gelatin capsules of suitablesize. Each capsule contains 200 mg of the active ingredient.

Any one of the other compounds embraced by formula I or a non-toxic,pharmacologically acceptable acid addition salt thereof may besubstituted for the particular active ingredient in Examples 8 and 9.Likewise, the amount of active ingredient in these illustrative examplesmay be varied to achieve the dosage unit range set forth above, and theamounts and nature of the inert pharmaceutical carrier ingredients maybe varied to meet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. A compound of the formula ##STR46## wherein R₁ is hydrogen,alkyl of 1 to 4 carbon atoms or trifluoromethyl;R₂, R₃ and R₄ are eachindependently hydrogen, methyl or ethyl; R₅ is hydrogen; alkyl of 1 to 8carbon atoms; phenyl-(alkyl of 1 to 8 carbon atoms); cycloalkyl of 3 to7 carbon atoms; (alkoxy of 1 to 4 carbon atoms) carbonyl methyl; phenyl;phenyl substituted by one to three identical or different substituentsselected from the group consisting of methyl, ethyl, methoxy, ethoxy,fluorine, chlorine, bromine and CF₃ ; naphthyl or naphthyl substitutedby one to three identical or different substituents selected from thegroup consisting of methyl, ethyl, methoxy, ethoxy, fluorine, chlorine,bromine and CF₃ ; and R₄ and R₅, together with each other, are alkyleneof 4 to 5 carbon atoms optionally interrupted by --O-- or --NR₆ --,where R₆ is alkyl of 1 to 4 carbon atoms; or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 2. A compoundof claim 1, whereR₁ is hydrogen or methyl, R₂, R₃ and R₄ are hydrogen;and R₅ is hydrogen, alkyl of 3 to 5 carbon atoms; cycloalkyl of 5 to 6carbon atoms, (alkoxy of 1 to 2 carbon atoms) carbonyl-methyl, phenyl,chlorophenyl, α-naphthyl, β-naphthyl or benzyl; or R₄ and R₅, togetherwith each other, are

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --NCH.sub.3 --CH.sub.2 --CH.sub.2 ;

or a non-toxic, pharmacologically acceptable acid addition salt thereof.3. A compound of claim 1, which is1-[6,7-dimethoxyquinazol-4-yl]-simicarbazide or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 4. A compoundof claim 1, which is1-n-butyl-4-(6,7-dimethoxyquinazol-4-yl)-simicarbazide or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 5. Acardiotonic pharmaceutical composition consisting essentially of aninert pharmaceutical carrier and an effective cardiotonic amount of acompound of claim
 1. 6. The method of increasing the cardiac output of awarm-blooded animal in need thereof, which comprises perorally orparenterally administering to said animal an effective cardiotonicamount of a compound of claim 1.